Tobacco use exerts a tremendous societal, healthcare and economic burden, and is the leading cause of preventable death in the United States. Extensive preclinical data indicates pharmacological stressors increase drug seeking/self-administration across drugs of abuse (including nicotine). Clinical translation of thi robust preclinical observation has been limited. My Sponsor (Dr. Greenwald) was first to demonstrate this finding in human substance users. Data from our lab indicate that pharmacological stressors produce a reliable physiological stress response, are medically safe, and increase drug seeking/self-administration. However, no published studies have investigated neurobiological mechanisms associated with stressor-potentiated drug seeking/self-administration. The goal of this application is to expand my Sponsor's work to investigate the effects of an acute pharmacological stress-induction on frontostriatal network function, neurochemistry, subjective internal state, and nicotine seeking/self-administration. The frontostriatal network (emanating from the dorsolateral prefrontal cortex [dlPFC]) is implicated in cognitive processes associated with nicotine seeking/self-administration, including: self-control, delayed gratification, and cigarette/smoking cue reactivity. Using a within-subject randomized crossover design, we will examine the effects of combined oral pretreatment with yohimbine [YOH: ?2-adrenoreceptor antagonist] and hydrocortisone [HYD: glucocorticoid agonist] relative to placebo [lactose] on frontostriatal network function, dlPFC neurochemistry, nicotine seeking/self-administration, and subjective effects (affect, anxiety, withdrawal and craving) among current smokers. Overall hypotheses: YOH+HYD pretreatment will induce a physiological stress response, reduce dlPFC engagement, uncouple dlPFC control of brain reward regions, attenuate glutamate response during cognitive task performance, and potentiate nicotine seeking/self- administration. The experimental design, methods, and hypotheses are based on the strong preliminary and published data from the Sponsor's laboratory and the scientific literature. Significance: Our approach will facilitate investigation f plausible neurobiological mechanisms associated with stressor-potentiated drug seeking/self-administration, an important and understudied clinical phenomenon. This project represents the first study of a programmatic line of inquiry into neurobiological mechanisms associated with drug seeking/self-administration. Potential future research studies would; A) expand YOH+HYD dose combinations, B) investigate other substance dependent populations (e.g. marijuana, cocaine), and pretreat with C) extended-release guanfacine (?2-adrenoreceptor agonist) or D) distress tolerance/relaxation techniques which may attenuate stressor-potentiated drug seeking/self-administration. I have assembled a collaborative team of mentors, each possessing unique expertise relevant to the current proposal, which will provide me a multidisciplinary training experience consistent with my career goals.